Method of diagnosing autism spectrum disorder

ABSTRACT

The present invention provides a method for diagnosing an autism spectrum disorder (ASD), or predisposition to develop an ASD, in a subject, which comprises the step of investigating a set of single nucleotide polymorphisms (SNPs) in a sample from the subject, wherein the number of SNPs in the set is such that the method can diagnose ASD with at least 70% accuracy. The invention also provides a kit for diagnosing an ASD, or predisposition to develop an ASD, in a subject, which comprises a plurality of primer pairs or probes capable of investigating such a set of SNPs in a sample from a subject, and a method for making such a kit.

FIELD OF THE INVENTION

The present invention relates to the diagnosis of Autism spectrumdisorder (ASD), or predisposition to develop ASD. In particular itrelates to a method for diagnosing an ASD, or predisposition to developan ASD, by investigating a set of single nucleotide polymorphisms (SNPs)in a sample from a subject.

BACKGROUND TO THE INVENTION

Autism Spectrum Disorders (ASDs) are a spectrum of neurodevelopmentalconditions characterized by impairments in social interaction andcommunication, and associated with repetitive, restricted patterns ofinterest or behaviour. Autism Spectrum Disorders is an umbrella termused to describe a number of autism disorders such as classic autism,Asperger's Syndrome, atypical autism and pervassive developmentaldisorder not otherwise specified.

ASDs are relatively common neurodevelopmental disorders, affectingapproximately 1% of the population. Autism shows a well establishedgender distortion with about four times as many males as females beingaffected.

Currently a diagnosis of ASD is formulated using behavioural criteria,with the aid of diagnostic manuals, for example the InternationalClassification of Disease (ICD-10) and Diagnostic and Statistic Manualof mental health (DSM-IV). The diagnosis of autism is not unified and anumber of distinct criteria are applied in different parts of the world.In many European countries diagnostic criteria like DSM-IV forpsychiatric diseases are applied. The Autism Diagnostic Interview (ADI)and Autism Diagnostic Observation Schedule (ADOS) are diagnostic tests,and have become a kind of ‘gold standard’ and are increasingly beingimplemented in both the USA and Europe.

The Autism Diagnostic Interview-Revised (ADI-R) is a diagnosticassessment for ASD. It is a parental interview that probes for language,social, behavioural, and functional abnormalities that are inconsistentwith a specific child's stage of development. The ADI-R is astandardized, semi-structured clinical review for caregivers of childrenand adults. The interview contains 111 items and focuses on behavioursin three content areas: quality of social interaction, (e.g., emotionalsharing, offering and seeking comfort, social smiling and responding toother children); communication and language (e.g., stereotypedutterances, pronoun reversal, social usage of language); and repetitive,restricted and stereotyped interests and behaviour (e.g., unusualpreoccupations, hand and finger mannerisms, unusual sensory interests).Responses are scored by the clinician based on the caregiver'sdescription of the child's behaviour. This interviewer-based instrumentrequires substantial training in administration and scoring, making itvery time-consuming and expensive. As diagnosis also depends on theassessment of both the caregiver and interviewer, it is also highlysubjective.

The main treatment proposed for ASDs are based on intensive educationalprograms, but also include pharmacotherapy and cognitive behaviouralapproaches. Sustained special education programs and behavior therapyearly in life can help children acquire self-care, social, and jobskills. Available approaches include applied behavior analysis (ABA),developmental models, structured teaching, speech and language therapy,social skills therapy, and occupational therapy. Applied early enough,studies have shown that as many as 50% of autistic childrenparticipating in such programs can be referred back to normal schoolingand education. In a recent UK study the potential socio-economic benefitof early intensive treatment has been estimated to be as high as £1.8million per patient over the life-time of the patient.

However, the age at which the therapy is provided and started is ofsignificant importance. Ideally, it is thought that the programs shouldstart at 18 months age, at the latest.

As outlined above, the ADI-R cannot be used for diagnosis under the ageof 18 months. Indeed, for infra-structural (availability of trainedexperts, in the US only 10% of suspected autistic children have directaccess to specialists able to carry out ADI-R) and social reasons theaverage age of diagnosis is 5 years in the US and 8 years in some partsof Europe.

Of importance also is that there is increasing recognition that manyadults with ASD have not been recognised or diagnosed. In adults,however, current symptoms are often modulated by coping strategiesdeveloped over the life-span, and retrospective accounts of pastsymptoms rely not only on the availability of an informant but also ontheir reliability. Moreover, for reasons of confidentiality, many adultsdo not wish others to be interviewed about their condition—and so a fulldiagnostic developmental history cannot be obtained to allow a confidentdiagnosis of ASD.

Hence there is a clear need for improved diagnostic methods for ASDswhich address the problems associated with the behaviouralcharacterisation studies currently in use. In particular, there is aneed for an early-detection method enabling early intervention, which isthought to be essential in order to have a significant impact on thechild's development.

DESCRIPTION OF THE FIGURES

FIG. 1—A graph to show the relationship between the number of SNPs usedin the diagnostic assay and the overall accuracy of ASDaffected/unaffected classification.

SUMMARY OF THE INVENTION

The present inventors have developed a new genetic test which candiagnose ASD with over 96% accuracy. The advantage of a genetic test isthat it can be conducted at any age, for example at birth or duringbabyhood, allowing appropriate educational programmes to be started inearly infancy and maximal benefit to be gained from such programs. Itcan also be applied in adulthood. A genetic test also does away with theneed for trained professional to carry out behavioural testing, andaddresses the problems associated with inconsistencies between thedifferent behavioural tests and subjectivity of thecaregiver/interviewer.

Thus, in a first aspect, the present invention provides a method fordiagnosing an autism spectrum disorder (ASD), or predisposition todevelop an ASD, in a subject, which comprises the step of investigatinga set of single nucleotide polymorphisms (SNPs) in a sample from thesubject, wherein the number of SNPs in the set is such that the methodcan diagnose ASD with at least 70% accuracy.

The set of SNPs may be at least partly derivable from the list of SNPsgiven in Table 3. For example, the set may comprise at least 1500 SNPs,at least 2300 SNPs or all 3126 SNPs from the list given in Table 3.

The set of SNPs may comprise at least 70% of the SNPs weighted at least±0.01 in Table 3.

The set of SNPs may comprise between 1500 and 4500 SNPs, between 2300and 3900 SNPs, or between 3000 and 3300 SNPs.

The set of SNPs may comprise one or more SNPs which are highlycorrelated with one or more SNPs from the list given in Table 3.

In a second aspect, the present invention provides a kit for diagnosingan autism spectrum disorder (ASD), or predisposition to develop an ASD,in a subject, which comprises a plurality of primer pairs or probescapable of investigating a set of single nucleotide polymorphisms (SNPs)in a sample from the subject, wherein the set of SNPs is as defined inaccordance with the first aspect of the invention.

Where the kit comprises a plurality of probes, they may be immobilisedon a solid support.

In a third aspect, the present invention provides a method for preparinga kit according to the second aspect of the invention which comprisesthe step of immobilising the plurality of probes on to a solid support.

DETAILED DESCRIPTION Autism Spectrum Disorder

Autism spectrum disorders (ASD) are developmental disorders resultingfrom dysfunction in the central nervous system and are characterized byimpairments in three behavioural areas: communication (including spokenlanguage), social interactions, and repetitive behaviours or restrictedinterests. ASDs usually manifest before three years of age and theseverity can vary greatly. Idiopathic ASDs currently include autism,which is considered to be the most severe form; pervasive developmentaldisorders not otherwise specified (PDD-NOS); and Asperger's syndrome, aform of autism in which persons can have relatively normal intelligenceand communication skills but difficulty with social interactions.

ASD may be diagnosed using behavioural criteria, with the aid ofdiagnostic manuals, for example the International Classification ofDisease (ICD-10) and Diagnostic and Statistic Manual of mental health(DSM-IV); or by using Autism Diagnostic Interview-Revised (ADI-R) whichis a diagnostic assessment for ASD.

The method of the present invention may be capable of diagnosing anautism spectrum disorder (ASD), for example it may be used to establishor confirm that a subject is affected by an ASD. In this embodiment, thesubject may already show symptoms of the ASD, such as impaired socialinteraction and/or communication, or repetitive patterns of interest orbehaviour.

The method of the present invention may be capable of diagnosing ordetecting a predisposition to develop an ASD. For example, it may beused to predict the likelihood that a subject will develop an ASD, maybebefore the subject shows one or more symptom(s) of an ASD. Thisembodiment is particularly useful for the evaluating the likelihood ofASD development in a subject too young for ASD examination usingclassical behavioural analysis, such as a subject less that 18 monthsold. Also it will allow diagnosis in people (e.g. adults or refugees)who have no informants available to confirm their developmental history.

Single Nucleotide Polymorphisms

As used herein, single-nucleotide polymorphism (SNP) is a DNA sequencevariation occurring when a single nucleotide (A, T, C, or G) in thegenome differs between an individual affected with an ASD and anunaffected individual.

Single nucleotides may be changed (substitution), removed (deletions) oradded (insertion) to a polynucleotide sequence. Insertion or deletionSNPs (InDels) may shift translational frame.

Single nucleotide polymorphisms may fall within coding sequences ofgenes, non-coding regions of genes, or in the intergenic regions betweengenes.

The method of the invention involves investigating a set of singlenucleotide polymorphisms (SNPs) in a sample from the subject. In otherwords, the presence of absence of a plurality of SNPs in a subject isanalysed, in order to give an overall “score” from which it can bededuced whether a subject has, or is likely to develop a predispositionto ASD.

SNPs may be defined by their position within the genome, for example asan “rs” number (see Table 3). Relevant sequence information may be foundfrom public databases such as http://genome.uscs.edu orhttp://www.ncbi.nlm.nih.gov/snp.

SNP Sets

Using the Autism Genetic Resource Exchange (AGRE) sample (see below),comprising 1385 individuals with ASD and 1494 unaffected individuals, awhole genome association study identified 390671 SNPs.

Subsequent analysis revealed that accuracy could be improved by using asub-set of this total number, including the most “influential” SNPs(i.e. those with the highest weighting). A SNP set consisting of the3126 SNPs listed in Table 3 gave an overall ASD classification accuracyof over 96.6%.

It is likely that small modifications to the number of SNPs in the setcan be made without significantly affecting accuracy. For example, thenine SNPs from Table 3 shown below:

-   -   rs7965985    -   rs753213    -   rs7403957    -   rs4698515    -   rs3923686    -   rs6908859    -   rs7794971    -   rs793091    -   SNP_A-1992337        are listed with a weighting of “0”, so it is likely that any or        all of these could be removed without affecting classification        accuracy.

It is believed, however that larger increases or decreases in the numberof SNPs in the set will decrease accuracy, but this may still be withinacceptable levels for a diagnostic test.

For example, as shown in Table 2, a SNP set comprising 2345 SNPsachieved an accuracy of 89% and a SNP set comprising 3907 SNPs achievedan accuracy of 89.09%.

In accordance with the present invention, the number of SNPs in the SNPset should be such that the accuracy of ASD classification is at least70%.

The SNP set may comprise at least 1500, at least 2300, or at least 3000SNPs from the list given in Table 3.

The SNP set may comprises substantially all 3126 SNPs given in Table 3.For example, the SNP set may comprise between 3110 and 3126 SNPs fromthe list given in Table 3.

The SNP set may comprises at least 70%, 80%, 90% or 95% of the SNPsweighted at least ±0.01 in Table 3.

The SNP set may comprises at least 70%, 80%, 90% or 95% of the SNPsweighted at least ±0.02 in Table 3.

The SNP set may comprises at least 70%, 80%, 90% or 95% of the SNPsweighted at least ±0.03 in Table 3.

The SNP set may comprises at least 70%, 80%, 90% or 95% of the SNPsweighted at least ±0.04 in Table 3.

The SNP set may comprise, for example, between 1500 and 4500, between2300 and 3900 SNPs, or between 3000 and 3300 SNPs.

Highly Correlated SNPS

The SNP set may comprise on or more SNPs which are highly correlatedwith one or more SNPs from the list given in Table 3 Linkagedisequilibrium (LD) is the measure of how correlated one SNP is toanother. Within the list of SNPs given in Table 3, a person skilled inthe art can calculate SNPs which will be in high correlation (LD) withthose SNPs, which in turn may be predictive for ASDs.

LD provides a score (r2) ranging from 0-1. A highly correlated SNP mayhave a score of at least 0.7, 0.8 or 0.9 based on the set of SNPs givenin Table 3.

Accuracy

The level of accuracy obtained using a given SNP set may be obtained bychallenging the SNP to diagnose ASD for a group of individuals whose ASDstatus is already known, for example by standard behaviouralclassification.

The % accuracy for a given SNP set may be obtained by:

number of correctly classified individuals/number of individuals×100

The group of individuals may comprise ASD affected subjects, ASDunaffected subjects or a combination of both types of subject. Where thegroup comprises both ASD affected and ASD unaffected subjects, the SNPset is challenged for its capacity to identify individuals both“positively” and “negatively”, providing a more robust result.

The group of individuals should be large enough to ensure that thecalculated accuracy levels are statistically significant. Too small atest group may not provide a complete picture of the significance of agiven result, whether it is a positive or negative correctclassification or a “false positive” or “false negative”.

The test group may, for example, comprise at least 100, 500 or 1000individuals.

The test group may be Autism Genetic Resource Exchange sample, asdescribed in the Examples.

It is also possible to measure both specificity and sensitivity asfollows:

Specificity: True negatives/True negatives+False positivesSensitivity: True positives/True positives+True negatives

The specificity of the SNP set may be at least 70%, at least 80%, atleast 85% or at least 90%.

The sensitivity of the SNP set may be at least 70%, at least 80%, atleast 85% or at least 90%.

SNP Investigation

The term “investigation” is used to mean that the presence or absence ofa SNP in a given genome is determined.

Applicable diagnostic techniques include, but are not limited to, DNAsequencing including mini-sequencing, primer extension, hybridizationwith allele-specific oligonucleotides (ASO), oligonucleotide ligationassays (OLA), PCR using allele-specific primers (ARMS), dot blotanalysis, flap probe cleavage approaches, restriction fragment lengthpolymorphism (RFLP), kinetic PCR, and PCR-SSCP, fluorescent in situhybridisation (FISH), pulsed field gel electrophoresis (PFGE) analysis,Southern blot analysis, single stranded conformation analysis (SSCA),denaturing gradient gel electrophoresis (DGGE), temperature gradient gelelectrophoresis (TGGE), denaturing HPLC (DHPLC), and RNAse protectionassays, all of which are known to the person skilled in the art.

For a known SNP, direct determination of the respective genotype isusually the method of choice. State of the art approaches for industrialhigh-throughput genotyping today rely on one of four differentmechanisms: allele-specific primer extension, allele-specifichybridization, allele-specific oligonucleotide ligation andallele-specific cleavage of a flap probe (K wok, Pharmacogenomics 1, 95(2000)). Sequencing or mini-sequencing protocols are part of the primerextension methods, e.g. genomic DNA sequencing, either manual or byautomated means. Minisequencing (primer extension) technology is basedon determining the sequence at a specific base by allowing theelongation of a primer by one base directly at the variant site(Landegren et al., Genome Res. 8: 769-76 (1998)). Short sequencereactions coupled with an alternative detection method are the nature ofreal time pyrophosphate sequencing (Nyren et al., Science 281:363(1998)).

Allele-specific hybridization protocols rely on probes detecting one orseveral of the alleles present at the SNP positions. Several techniqueswere developed for detection of a hybridization event. In the 5′nuclease assay and in the molecular beacon assay, the hybridizationprobes are fluorescently labelled and probe binding is detected viachanges in the behaviour of the fluorescent label (Livak, Genet. Anal.14, 143 (1999); Tyagi et al., Nat. Biotechnol. 16, 49 (1998)).Hybridization events may occur in liquid phase or with either the probeor the target bound to a solid surface.

An array (microchip) typically consists of thousands of distinctnucleotide probes which are built up in an array on a silicon chip.Nucleic acid to be analyzed is fluorescently labelled, and hybridized tothe probes on the chip. This method is one of parallel processing ofthousands of probes at once and can tremendously accelerate theanalysis. In several publications the use of this method is described(Hacia et al., Nature Genetics 14, 441 (1996); Shoemaker et al., NatureGenetics 14, 450 (1996); Chee et al., Science 274, 610 (1996); DeRisi etal., Nature Genetics 14, 457 (1996), Fan et al., Genome Res, 10, 853(2000)).

Allele-specific oligonucleotide ligation assays have a high specificity.Oligonucleotides differing in the allele-specific base at the 5′- or3′-end are only processed in a ligation reaction if they are perfectlybound to the template at the respective oligonucleotide end. This methodhas been coupled with fluorescence resonance energy transfer (FRET)labeling to create a homogeneous assay system (Chen et al. Genome Res.8, 549 (1998)). Allele-specific cleavage of a flap probe use theproperty of recently discovered flap endonucleases (cleavases) to cleavestructures created by two overlapping oligonucleotides. In this approachtwo overlapping oligonucleotides are bound to the polymorphic site. Thatoligo which has had a perfect match to the target sequence is thendetected by the cleavage reaction (Lyamichev et al., Nat. Biotechnol.17:292 (1999)). Other methods which detect specific base variationsusually allow only a lower throughput, such as the allele-specificoligonucleotide (ASO) hybridization. For allele-specific PCR, primersare used which hybridize at their 3′ ends to the target sequence. Onlyfor alleles which are present, a respective PCR product is generated(Ruano and Kidd, Nucleic Acids Res 17, 8392 (1989)). A specificityincreasing modification of allele-specific PCR is the AmplificationRefractory Mutation System, as disclosed in European Patent ApplicationPublication No. 0332435 and in Newton et al., Nucleic Acids Res 17, 2503(1989). If the variations lead to changes in the specific recognitionsites of nucleic acid processing, enzymes methodologies such asrestriction fragment length polymorphism (RFLP) probes or PCR-RFLPmethods may also be used to detect these variations.

Detection of SNPs may be accomplished by amplification, for instance byPCR, from genomic or cDNA and sequencing of the amplified nucleic acidor by molecular cloning of the relevant allele and sequencing the alleleusing techniques well known in the art.

Kit

The present invention also provides kit for diagnosing an autismspectrum disorder (ASD), or predisposition to develop an ASD, in asubject, which comprises a plurality of primer pairs or probes capableof investigating a set of single nucleotide polymorphisms (SNPs) in asample from the subject, wherein the set of SNPs is as defined above.

The kit may comprise a plurality of probes, each capable of hybridisingspecifically to one of the alternative forms of the SNP.

As used herein, the term “probe” refers to a nucleic acid (eg. anoligonucleotide or a polynucleotide sequence) that is complementary to anucleic acid sequence present in a sample, such that the probe willspecifically hybridize to the nucleic acid sequence present in thesample under appropriate conditions.

The kit may also comprise means for detecting the presence of aplurality of hybridization products, corresponding to each probe/SNPcombination.

The probes may be gene probes, for example oligomeric DNA sequences of15 to 50 bases which are synthesized with a variant base, to detect thepresence of a SNP, or no variant bases, to detect the absence of a SNP.

The probe is then hybridized to the genome under stringent conditionsallowing single base variant discrimination.

Alternatively the kit may comprise a plurality of primer pairs, usingwhich each SNP may detected by:

a) amplifying the potential SNP-containing parts of the nucleic acid insaid sample,b) sequencing, e.g. mini-sequencing, the amplified nucleic acids; andc) detecting the presence or absence of the SNPs in said sample.

The term “primer” as used herein refers to an oligonucleotide which iscapable of acting as a point of initiation of synthesis when placedunder conditions in which synthesis of a primer extension product whichis complementary to a nucleic acid strand is induced, i.e. in thepresence of nucleotides and an inducing agent—such as DNA polymerase andat a suitable temperature and pH.

The primers and/or probes may be labelled in order to facilitate theirdetection. Such labels (also known as reporters) include, but are notlimited to, radioactive isotopes, fluorophores, chemiluminescentmoieties, enzymes, enzyme substrates, enzyme cofactors, enzymeinhibitors, dyes, metal ions, metal sols, other suitable detectablemarkers—such as biotin or haptens and the like. Particular example oflabels which may be used include, but are not limited to, fluorescein,5(6)-carboxyfluorescein, Cyanine 3 (Cy3), Cyanine 5 (Cy5), rhodamine,dansyl, umbelliferone, Texas red, luminal, NADPH and horseradishperoxidase.

The probes and/or primers used in the kit hybridise specifically totheir target nucleic acid sequence. They may, for example, hybridiseunder high-stringency conditions.

Stringency of hybridisation refers to conditions under which polynucleicacids hybrids are stable. Such conditions are evident to those ofordinary skill in the field. As known to those of skill in the art, thestability of hybrids is reflected in the melting temperature (Tm) of thehybrid which decreases approximately 1 to 1.5° C. with every 1% decreasein sequence homology. In general, the stability of a hybrid is afunction of sodium ion concentration and temperature.

As used herein, high stringency refers to conditions that permithybridisation of only those nucleic acid sequences that form stablehybrids in 1M Na+ at 65-68° C. High stringency conditions can beprovided, for example, by hybridisation in an aqueous solutioncontaining 6×SSC, 5×Denhardt's, 1% SDS (sodium dodecyl sulphate), 0.1Na+ pyrophosphate and 0.1 mg/ml denatured salmon sperm DNA as nonspecific competitor.

It is understood that these conditions may be adapted and duplicatedusing a variety of buffers, e.g. formamide-based buffers, andtemperatures. Denhardt's solution and SSC are well known to those ofskill in the art as are other suitable hybridisation buffers (see, e.g.Sambrook, et al., eds. (1989) Molecular Cloning: A Laboratory Manual,Cold Spring Harbor Laboratory Press, New York or Ausubel, et al., eds.(1990) Current Protocols in Molecular Biology, John Wiley & Sons, Inc.).Optimal hybridisation conditions have to be determined empirically, asthe length and the GC content of the hybridising pair also play a role.

Sample

The sample may be or may be derived from a biological sample, such as ablood sample, cheek swab, a biopsy specimen, a tissue extract, an organculture or any other tissue or cell preparation from a subject.

In theory, the presence of SNP can be determined by extracting DNA fromany tissue of the body.

The sample may be or may be derived from an ex vivo sample.

The sample may be or may be derived from whole blood or a fraction ofwhole blood.

Suitably, the sample is nucleic acid, such as genomic DNA.

Subject

The subject may be a human. The subject may be a child under 10 years ofage. The subject may be a child whose age or mental age is too low forreliable ASD assessment using behavioural tests. For example, thesubject may be a child under 18 months of age. Additionally the subjectmay be an adolescent or adult.

The subject may be pre-implantation or post-implantation foetus.

Foetal cells for analysis can be obtained by amniocentesis, chorionicvillus sampling (CVS), or drawing blood from the foetal umbilical cord,using methods known in the art. Pre-natal testing allows the likelihoodof a subject to develop an ASD to be determined before birth, so thisinformation can be taken into consideration throughout the child'sbabyhood and infancy.

Pre-implantation screening may be carried out, for example, during IVFprocedures. Genetic material for analysis may be obtained, for example,from polar bodies using known techniques.

The subject may show some symptoms of an ASD. The subject may have beenpreviously characterised as having an ASD by behavioural tests. Wherethe results of behavioural tests are ambiguous or inconclusive, themethod of the present invention may be used to confirm the diagnosis.

The subject may have a family history of ASD.

Solid Support

In the kit of the present invention, nucleic acid probes may beassociated with a support or substrate to provide an array of nucleicacid probes to be used in an array assay. Suitably, the probe ispre-synthesized or obtained commercially, and then attached to thesubstrate or synthesized on the substrate, i.e., synthesized in situ onthe substrate.

A specific method of nucleic acid hybridization that can be utilized isnucleic acid chip/array hybridization in which nucleic acids are presenton a immobilized surface—such as a microarray and are subjected tohybridization techniques sensitive enough to detect minor changes insequences.

As used herein, an “array” includes any two-dimensional or substantiallytwo-dimensional (as well as a three-dimensional) arrangement ofaddressable regions bearing a particular chemical moiety or moieties(e.g., biopolymers—such as polynucleotide or oligonucleotide sequences(nucleic acids), polypeptides (e.g., proteins), carbohydrates, lipids,etc.). The array may be an array of polymeric binding agents—such aspolypeptides, proteins, nucleic acids, polysaccharides or syntheticmimetics. Typically, the array is an array of nucleic acids, includingoligonucleotides, polynucleotides, cDNAs, mRNAs, synthetic mimeticsthereof, and the like. Where the arrays are arrays of nucleic acids, thenucleic acids may be covalently attached to the arrays at any pointalong the nucleic acid chain, but are generally attached at one of theirtermini (e.g. the 3′ or 5′ terminus). Sometimes, the arrays are arraysof polypeptides, e.g., proteins or fragments thereof.

Array technology and the various techniques and applications associatedwith it is described generally in numerous textbooks and documents.These include Lemieux et al., 1998, Molecular Breeding 4, 277-289,Schena and Davis. Parallel Analysis with Biological Chips. in PCRMethods Manual (eds. M. Innis, D. Gelfand, J. Sninsky), Schena andDavis, 1999, Genes, Genomes and Chips. In DNA Microarrays: A PracticalApproach (ed. M. Schena), Oxford University Press, Oxford, UK, 1999),The Chipping Forecast (Nature Genetics special issue; January 1999Supplement), Mark Schena (Ed.), Microarray Biochip Technology, (EatonPublishing Company), Cortes, 2000, The Scientist 14[17]:25, Gwynne andPage, Microarray analysis: the next revolution in molecular biology,Science, 1999 Aug. 6; and Eakins and Chu, 1999, Trends in Biotechnology,17, 217-218.

Array technology overcomes the disadvantages with traditional methods inmolecular biology, which generally work on a “one gene in oneexperiment” basis, resulting in low throughput and the inability toappreciate the “whole picture” of gene function. Array technology may beused in the context of the present invention to identify the presence orabsence of some or all of the SNPs from the SNp set in the sample fromthe subject.

The SNP detection system (e.g. probes) may be fixed or immobilised ontoa solid phase, preferably a solid substrate, to limit diffusion andadmixing of the samples. Probes may be immobilised to a substantiallyplanar solid phase, including membranes and non-porous substrates suchas plastic and glass. Furthermore, the probes may be arranged in such away that indexing (i.e., reference or access to a particular SNP) isfacilitated. Typically the probes are applied as spots in a gridformation. Common assay systems may be adapted for this purpose. Forexample, an array may be immobilised on the surface of a microplate,either with multiple probes in a well, or with a single probe in eachwell. Furthermore, the solid substrate may be a membrane, such as anitrocellulose or nylon membrane (for example, membranes used inblotting experiments). Alternative substrates include glass, or silicabased substrates. Thus, the probes are immobilised by any suitablemethod known in the art, for example, by charge interactions, or bychemical coupling to the walls or bottom of the wells, or the surface ofthe membrane. Other means of arranging and fixing may be used, forexample, pipetting, drop-touch, piezoelectric means, ink-jet andbubblejet technology, electrostatic application, etc. In the case ofsilicon-based chips, photolithography may be utilised to arrange and fixthe probes on the chip.

The samples may be arranged by being “spotted” onto the solid substrate;this may be done by hand or by making use of robotics to deposit thesample. In general, arrays may be described as macroarrays ormicroarrays, the difference being the size of the sample spots.Macroarrays typically contain sample spot sizes of about 300 microns orlarger and may be easily imaged by existing gel and blot scanners. Thesample spot sizes in microarrays are typically less than 200 microns indiameter and these arrays usually contain thousands of spots. Thus,microarrays may require specialized robotics and imaging equipment,which may need to be custom made. Instrumentation is described generallyin a review by Cortese, 2000, The Scientist 14[11]:26. The number ofdistinct nucleic acid sequences, and hence spots or similar structures(i.e., array features), present on the array may vary, but is generallyat least 2, usually at least 5 and more usually at least 10, where thenumber of different spots on the array may be as a high as 50, 100, 500,1000, 10,000 or higher, depending on the intended use of the array. Thespots of distinct nucleic acids present on the array surface aregenerally present as a pattern, where the pattern may be in the form oforganized rows and columns of spots, e.g., a grid of spots, across thesubstrate surface, a series of curvilinear rows across the substratesurface, e.g., a series of concentric circles or semi-circles of spots,and the like. The density of spots present on the array surface mayvary, but will generally be at least about 10 and usually at least about100 spots/cm², where the density may be as high as 10⁶ or higher, butwill generally not exceed about 10⁵ spots/cm².

Techniques for producing immobilised libraries of DNA molecules havebeen described in the art. Generally, most prior art methods describedhow to synthesise single-stranded nucleic acid molecule libraries, usingfor example masking techniques to build up various permutations ofsequences at the various discrete positions on the solid substrate. U.S.Pat. No. 5,837,832, describes an improved method for producing DNAarrays immobilised to silicon substrates based on very large scaleintegration technology. In particular, U.S. Pat. No. 5,837,832 describesa strategy called “tiling” to synthesize specific sets of probes atspatially-defined locations on a substrate which may be used to producedthe immobilised DNA libraries of the present invention. U.S. Pat. No.5,837,832 also provides references for earlier techniques that may alsobe used.

The array will include a plurality of different probes of differentsequence covalently or non-covalently attached to, different and knownlocations on the substrate surface. The array may comprise a probe foreach SNP in the SNP set.

To aid detection, targets and probes may be labelled with any readilydetectable reporter, for example, a fluorescent, bioluminescent,phosphorescent, radioactive, etc reporter. Such reporters, theirdetection, coupling to targets/probes, etc are discussed elsewhere inthis document. Labelling of probes and targets is also disclosed inShalon et al., 1996, Genome Res 6(7):639-45

Specific examples of DNA arrays are as follow:

Format I: probe cDNA (5005,000 bases long) is immobilized to a solidsurface such as glass using robot spotting and exposed to a set oftargets either separately or in a mixture. This method is widelyconsidered as having been developed at Stanford University (Ekins andChu, 1999, Trends in Biotechnology, 1999, 17, 217-218).

Format II: an array of oligonucleotide (20-25-mer oligos) or peptidenucleic acid (PNA) probes is synthesized either in situ (on-chip) or byconventional synthesis followed by on-chip immobilization. The array isexposed to labeled sample DNA, hybridized, and the identity/abundance ofcomplementary sequences are determined. Such a DNA chip is sold byAffymetrix, Inc., under the GeneChip® trademark.

Data analysis is also an important part of an experiment involvingarrays. The raw data from a microarray experiment typically are images,which need to be transformed into gene expression matrices—tables whererows represent for example genes, columns represent for example varioussamples such as tissues or experimental conditions, and numbers in eachcell for example characterize the expression level of the particulargene in the particular sample. These matrices have to be analyzedfurther, if any knowledge about the underlying biological processes isto be extracted. Methods of data analysis (including supervised andunsupervised data analysis as well as bioinformatics approaches) aredisclosed in Brazma and Vilo J (2000) FEBS Lett 480(1):17-24.

SNPs may be detected using the BeadXpress Reader System (Illumina Inc.,North America). See for example, U.S. Pat. No. 6,355,431. This system isa high-throughput, dual-colour laser detection system that enablesscanning of a broad range of multiplexed assays developed using theVeraCode digital microbead technology. Unique VeraCode microbeads arescanned for their code and fluorescent signals, generating highly robustdata quickly and efficiently. Downstream analysis is conducted usingIllumina's BeadStudio data analysis software or other third-partyanalysis programs.

The invention will now be further described by way of Examples, whichare meant to serve to assist one of ordinary skill in the art incarrying out the invention and are not intended in any way to limit thescope of the invention.

EXAMPLES Example 1 SVM Analysis of SNPs in Sample Comprising ASDAffected and Unaffected Individuals

Analysis of all individuals in the AGRE sample (see Materials andMethods), ‘Affected’ and ‘Unaffected’, using the ‘leave one out’ method,resulted in an overall accuracy of 87.6%, i.e. the algorithm predictedthe correct diagnostic class for 87.6% of the total sample. Thepercentage accuracy was higher in affected individuals than inunaffected individuals (Table 1).

TABLE 1 Overall classification of all AGRE samples. Total Sample (n)Predicted (n) Accuracy (%) ASD Affected 1385 1264 91.3 Unaffected 14941253 83.9 Total 2879 2517 87.6 Total sample: the total number ofindividuals in each diagnostic class. Predicted: the total numbercorrectly predicted by the SVM algorithm. Accuracy: the total percentageaccuracy achieved.

Using the following formulas, both specificity and sensitivity weremeasured:

Specificity: True Negatives/True Negatives+False Positives=84%Sensitivity: True Positives/True Positives+True Negatives=92%

Of the 121 ASD individuals who were misclassified, 42 were twins (41 MZ& 1 DZ) and an additional 4 individuals were quadruplets. 23 of theindividuals had a diagnosis of broader autism. 2 of the individualsmisclassified had an original diagnosis of autism, however AGRE did notconfirm these diagnoses upon their own assessments.

This supports the key assertions behind the invention that (i)clinicians make mistakes using standard diagnostic procedures; and (ii)genetic testing may be used to detect and correct these errors.

Example 2 Analysis with a Reduced Number of “Influential” SNPs

The whole genome sample described in Example 1 used a total of 390671SNPs to achieve an overall accuracy of 87.6%. Subsequent analysisinvolved identifying, from the initial analysis, which were mostinfluential to the classification, and repeating the analysis with areduced number of “influential” (i.e. more highly weighted) SNPs.

The results are shown in FIG. 1 and Table 2.

TABLE 2 No of SNPs Accuracy % 390671 87.43 78134 86.73 39067 75.82 1953458.18 7813 52.07 3907 89.09 3126 96.67 2345 89.00 1564 73.00

As shown in FIG. 1 and Table 2, maximal accuracy of over 96.6% isachieved with a SNP set of about 3126 of the most highly weighted SNPsfrom the whole genome sample. These SNPs, together with their respectiveweights, are shown in Table 3.

Increasing or decreasing the number of SNPs lowers the accuracy of thetest, but SNP sets containing between 2345 and 3907 SNPs still result inan accuracy of at least 89%.

Materials and Methods Sample

The Autism Genetic Resource Exchange (AGRE) sample was used, comprisingof 1385 individuals with ASD and 1494 unaffected individuals. A total of720 families were analysed, with at least one child diagnosed withautism using the ADI-R. The second (and subsequent) affected child hadan AGRE classification of autism, broad spectrum (including Asperger'sSyndrome and PDD-NOS) or Not Quite Autism (NQA, individuals who are nomore than one point away from meeting autism criteria on any or all ofthe diagnostic domains). Ethnicity and race was self-reported at 69%white, 12% Hispanic/Latino, 10% Unknown, 5% mixed, 2.5% each Asian andAfrican American, less than 1% Native Hawaiian/Pacific Islander andAmerican Indian/Native Alaskan.

Within the total sample, one set of quadruplets', all diagnosed withautism were evident. Six sets of triplets (14 Autism/1 NQA/3Unaffected), 43 dizygotic and 32 monozygotic twin pairs were noted (1additional twin pair set, of unknown zygosity was also sampled). Of theindividual twins, diagnosis was as follows—123 autism, 12 broadspectrum, 6 NQA, 4 unknown and 7 unaffected. Overall the diagnosticbreak down of all ASD individuals comprised of 87% autism, 8% broadspectrum and 5% NQA.

Genotyping was conducted using Affymetrix 5.0 chips at the GeneticAnalysis Platform of the Broad Institute; full methods are described in(Weiss, L. A., Y. Shen, et al. (2008). N Engl J Med 358(7): 667-75).

Data was downloaded from www.agre.org, comprising of three files

-   -   1) .bed—file comprising all generated genotype data    -   2) .bim—map of all genotyped markers    -   3) .fam—family structures of all individuals genotyped        From the .bed file, all SNPs found on the X and Y chromosomes        were removed. Due to the high ratio of males to females        diagnosed with ASD, it was though this in itself may be        influential in the classification. The .bed file was divided        into 2879 files, containing genotypic data for one individual.

Support Vector Machine

A SVM analysis, using a linear kernel, was applied to the data using aleave-one-out procedure. In this procedure a single individual iswithheld from the SVM training and then tested to assess whether theyare affected or unaffected. The leave-one-out procedure was subsequentlyrepeated 2879 times (for each individual) and the results averaged.

TABLE 3 SNP Weight rs626479 −0.0172 rs6680471 −0.0179 rs6665853 0.0136rs4654500 −0.0002 rs4654511 0.0146 rs12078298 0.0029 rs2411738 −0.0024rs12049256 0.0126 rs9439603 0.0332 rs2312464 0.007 rs17030082 −0.0119rs6679134 0.0119 rs2506902 0.0056 rs1292657 0.0323 rs2487647 0.0312rs2744692 0.0198 rs6694657 −0.0023 rs10927602 0.0225 rs6693417 0.0224rs17471689 0.0345 rs1934057 0.0119 rs732725 −0.0274 rs2744749 0.0178rs11249045 −0.0059 rs10794668 0.0123 rs430022 0.0113 rs311480 −0.0118rs566421 −0.0161 rs4908393 0.0105 rs4654352 0.0103 rs7547083 −0.022rs6426343 −0.0066 rs10753264 0.0107 rs669216 0.0206 rs2796209 −0.0063rs9659735 −0.0331 rs6696621 −0.0031 rs2180133 −0.0341 rs7517274 −0.0307rs16825353 −0.0078 rs10493109 0.0106 rs1034268 0.0056 rs7518522 −0.0288rs7365614 0.0267 rs264025 0.0081 rs945179 0.0239 rs3766212 0.0178rs1502908 −0.0032 rs1967757 −0.0007 rs835342 −0.0172 rs1288332 0.0108rs1288587 −0.0191 rs953625 0.0054 rs6683597 −0.0282 rs11206407 0.0034rs689258 −0.014 rs570218 0.0178 rs498831 0.0165 rs1749859 −0.0087rs3815226 −0.0023 rs590621 0.0023 rs13374752 0.0281 rs3992634 0.0197rs1331855 0.0264 rs706370 −0.0104 rs1557061 0.0153 rs3005896 0.0012rs12138574 0.0033 rs4477326 0.0222 rs4912230 0.0236 rs1524707 0.0257rs4244011 −0.0018 rs2760484 0.0325 rs6679571 0.0214 rs585368 −0.02rs11207575 0.0167 SNP_A- −0.0021 4277480 rs11207831 −0.0086 rs10889383−0.0088 rs6662848 −0.004 rs2179811 −0.0227 rs6588064 0.0146 rs825191−0.0152 rs2186122 −0.0038 rs7551528 0.0004 rs7516251 0.0142 rs2815351−0.0063 rs17375018 0.0327 rs12083789 −0.032 rs288929 0.0061 rs6173440.0092 rs11209455 0.0106 rs10736412 0.0198 rs11162095 0.0343 rs9970671−0.0282 rs4949764 −0.0111 rs10493649 −0.0022 rs17105569 0.0247rs10874241 −0.0312 rs7542573 −0.0193 rs12057556 −0.0203 rs772604 0.0247rs10782601 −0.0071 rs6662386 −0.0021 rs1188909 −0.0228 rs4414050 0.0123rs2249591 −0.031 rs12565150 −0.0068 rs12132107 0.0028 rs2064662 0.0043rs6693882 0.0195 rs1889060 −0.0212 rs12757095 −0.0299 rs387176 0.0194rs396954 0.0198 rs12137571 −0.0226 rs2336015 0.0066 rs11577194 0.0076rs17631306 0.0158 rs3393 0.0183 SNP_A- 0.0231 1962128 rs11102368 −0.0063rs4839202 −0.0054 rs11102374 −0.0197 rs2998359 −0.0262 rs4838994 0.0277SNP_A- 0.0168 4240881 rs12145661 −0.009 rs568359 0.0102 rs4659126 0.0069rs1325939 0.0231 rs2275236 −0.0252 rs10494273 0.0233 rs6587671 −0.0089rs1923496 −0.0158 rs2146116 −0.0039 rs10908448 −0.0233 rs954916 −0.0101rs9427242 0.0002 rs822430 0.0088 rs4661138 0.0121 rs11265186 −0.0272rs2501348 0.0104 rs4596880 −0.0061 rs2490438 0.0084 rs10919117 −0.0135rs2661810 −0.0058 rs11580624 −0.0167 rs10753642 0.0012 rs1494409 0.0172rs1494408 −0.0016 rs6675438 −0.0205 rs1343546 0.0138 rs2027573 0.019rs6697712 −0.0012 rs6426958 0.0071 rs1532482 0.0145 rs869714 0.0057rs885458 −0.011 rs2143312 0.0074 rs10918931 −0.007 rs16863926 −0.0196rs2224396 0.0179 rs12075807 0.0025 rs484686 −0.0337 rs912300 0.0264rs6694387 0.0145 rs9425287 −0.0049 rs6689901 0.0121 rs10732999 0.0205rs10913355 0.0273 rs12033565 −0.0189 rs7522303 −0.001 rs2811280 −0.0054rs1570807 0.0144 rs3845427 0.0159 rs477956 −0.0165 rs6703122 0.0068rs6692352 −0.005 rs6704003 −0.012 rs10911583 0.0191 rs6424983 −0.0263rs10801058 0.0304 rs1568133 0.0114 rs16836373 −0.0067 rs634727 −0.018rs10733086 −0.0013 rs1332660 0.0176 rs2224873 −0.0369 rs2359372 0.0093rs3767735 0.0352 rs1892432 0.003 rs2249156 −0.0006 rs2248967 −0.0006rs1572789 −0.0126 rs6700264 0.0191 rs2486933 0.0146 rs2486942 −0.0074rs4543864 0.0173 rs1997034 0.0178 rs2282450 −0.0065 rs12407361 −0.0078rs11579772 −0.0008 rs7552993 0.0033 rs684431 0.0107 rs1933573 −0.0169rs3753522 0.0057 rs1962735 0.0239 rs2294850 −0.0073 rs926579 0.0037rs10863900 −0.0007 rs4951534 0.0229 rs1509866 0.0154 rs11117658 0.0307rs11117796 −0.0148 rs1602269 −0.0023 rs2798631 0.0174 rs10863404 −0.0094rs4428898 −0.023 rs6694088 0.0098 rs2210977 −0.0024 rs2970199 −0.0255rs2790762 0.0019 rs6679430 0.0233 rs6676201 −0.0041 rs710824 −0.0151rs10916464 −0.0109 rs7538437 −0.014 rs1160075 −0.0268 rs867844 −0.0214rs6698696 0.0051 rs549209 −0.0044 rs6659304 0.0055 rs4659838 −0.022rs291356 −0.0072 rs2853599 −0.01 rs2385494 −0.0077 rs1266164 0.006rs1252252 0.0001 rs4659743 0.0021 rs10802581 −0.0097 rs4659491 −0.009rs16835116 0.011 rs7525233 −0.0271 rs6657299 −0.0227 rs1984165 0.007rs10926147 −0.0228 rs1539098 0.0146 rs3765814 −0.0013 rs6669036 0.0049rs6696527 −0.0018 rs2809979 −0.0081 rs10926897 0.0217 rs544739 −0.0016rs2786694 −0.0119 rs1093961 0.0034 rs1069217 0.0056 rs10924359 −0.0218rs3124124 0.0171 rs6671004 0.0129 rs2386548 −0.0136 rs1144812 0.0244rs4382761 −0.0093 rs1364648 0.0155 rs1451196 0.0086 rs6738683 0.0168rs6548128 −0.0314 rs10174005 0.0115 rs792105 −0.0052 rs7604344 −0.0249rs1381514 0.0102 rs1461312 −0.0205 rs13382991 −0.001 rs10167072 −0.0093rs17681545 0.0194 rs7572345 0.0197 rs328634 −0.0259 rs1003187 −0.0094rs4668666 −0.0266 rs6432085 −0.0011 rs16856887 0.0039 rs7594176 −0.0297rs10167277 −0.0033 rs1225214 0.0352 rs6432270 0.0071 rs17344070 −0.0206rs2571642 −0.0347 rs10189450 0.0221 rs10803676 0.0235 rs13385499 −0.0305rs12714264 0.0071 rs312970 0.0016 rs576203 0.0065 rs7570872 −0.0207rs11127215 −0.0142 rs207413 −0.0111 rs212708 0.0102 rs1534350 0.0018rs4670550 0.0013 rs1015696 −0.0171 rs7588747 0.0251 rs173023 −0.0186rs13010748 0.0096 rs297150 −0.0056 rs7582507 −0.0215 rs6746891 0.0119rs11688286 0.0207 rs1517024 0.0361 rs4082957 −0.0028 rs17033378 0.0165rs11678872 0.016 rs12712996 0.0064 rs1574380 0.0048 rs6738387 −0.0048rs2300443 −0.0124 rs13000157 −0.0153 rs7355586 −0.0374 rs17489439−0.0243 rs1159982 0.006 rs12328023 0.0287 rs7557799 0.0276 rs2033411−0.0211 rs4672103 −0.0027 rs11673760 −0.0195 rs820985 0.0133 rs7592500.0345 rs11691214 −0.0023 rs4671398 −0.0061 rs1011066 −0.0029 rs17692393−0.0008 rs2540959 −0.0126 rs1420183 −0.0284 rs11678288 0.0036 rs719832−0.0111 rs6743599 −0.0051 rs3771527 0.0125 rs12617676 −0.0058 rs4852430−0.0143 rs4510249 0.0007 rs1455385 0.0065 rs6738834 −0.0101 rs170222880.0106 rs6749875 0.0355 rs11689667 −0.0103 rs883650 −0.0062 rs9677221−0.0079 rs6738956 −0.0114 rs9309628 −0.0345 rs17704088 −0.0072 rs67133100.0046 rs921423 0.0167 rs1010387 0.0322 rs4632400 0.0056 rs17493655−0.0018 rs11686712 −0.0126 rs11683001 −0.0431 rs4603782 0.0026rs12712130 0.0053 rs1861228 −0.0229 rs12998183 −0.015 rs6543426 0.0031rs1524297 0.0081 rs1524287 0.0079 rs4676274 −0.0125 rs6754115 −0.0191rs884448 0.0104 rs10181720 0.0236 rs17047362 −0.0024 rs6737733 0.004rs1433526 −0.0105 rs17584619 −0.0147 rs10207133 −0.0125 rs116795890.0068 rs718867 0.017 rs297479 −0.017 rs299566 −0.0109 rs13002629−0.0133 rs12468639 −0.0112 rs11123081 −0.0233 rs13390374 0.0356 rs831360−0.0116 rs3820757 0.0187 rs4150477 0.009 rs840875 −0.0212 rs75782530.0087 rs7586789 0.0169 rs6431151 0.0241 rs6749712 0.0011 rs6727803−0.0171 rs1446749 0.0114 rs16831992 0.0075 rs936835 −0.0145 rs4437190.0337 rs10197153 −0.0294 rs351673 0.0042 rs9287378 0.0115 rs13421583−0.0263 rs6430136 0.0004 rs1356738 0.0334 rs1519768 0.0137 rs1519800−0.0112 rs298247 −0.0078 rs16842681 −0.0024 rs12692654 −0.0037 rs13692520.0005 rs2083482 −0.0345 rs4340537 0.0048 rs6732793 −0.0132 rs15408210.0156 rs700542 0.0235 rs17251018 0.0007 rs741378 0.019 rs7590275−0.0045 rs10206361 0.0189 rs2194720 0.0091 rs3754764 0.0147 rs21138070.0271 rs4893825 0.0445 rs4893966 0.0232 rs6751992 −0.0034 rs2600590.0244 rs10186570 −0.0158 rs12466031 −0.0348 rs2368384 −0.0149rs11902682 −0.0012 rs826168 −0.0311 rs7560722 0.0057 rs10166420 0.0297rs887701 −0.0161 rs1378156 −0.0215 rs4853575 −0.0173 rs7558504 −0.0068rs10931635 −0.0123 rs1392658 0.0158 rs11888904 −0.0154 rs7558972 −0.0314rs12614240 0.0117 rs295134 0.0197 rs4233996 0.0039 rs295149 0.0309rs1369841 0.0181 rs11892551 −0.0171 rs6757529 0.0117 rs10195536 −0.0232rs3820901 0.0144 rs16844213 0.0098 rs3821136 −0.022 rs10167685 0.015rs2662683 −0.0284 rs4673821 0.0126 rs12612329 −0.0136 rs828910 0.0079rs17779951 0.0155 rs750764 −0.0123 rs17226763 −0.0064 rs6723377 0.0106rs6733393 −0.0056 rs1371551 0.0095 rs3845841 0.0072 rs1596395 0.0107rs9288601 −0.0184 rs10208046 0.0171 rs6744449 0.0087 rs3811514 −0.0451rs6436790 0.0171 rs3106301 0.0177 rs6437020 0.0145 rs13395911 −0.0165rs689101 −0.0064 rs972513 0.0132 rs2316434 0.0076 rs7571980 −0.0146rs2292708 0.0099 rs10192532 −0.0154 rs2573712 0.0297 rs10187736 −0.0219rs821501 −0.0279 rs7608438 −0.0093 rs2648466 0.0306 rs1827106 −0.0078rs11128826 −0.0376 rs4434131 −0.0194 rs1143977 −0.0028 rs1032783 0.002rs1666325 −0.0204 rs17018141 0.004 rs427502 −0.0226 rs17023520 −0.0172rs4685803 0.0167 rs3804992 −0.0004 rs7637793 0.0029 rs11130339 −0.023rs286588 0.0053 rs10490889 0.0086 rs2117788 0.0025 rs5010733 −0.0233rs571701 −0.0125 rs341795 −0.0003 rs420537 −0.0238 rs709165 −0.0188rs299651 −0.0022 rs1618545 0.0136 rs2633442 0.0035 rs9831765 0.0225rs2881980 0.0149 rs4684901 0.0128 rs4684131 0.0147 rs9865654 0.0164rs981694 0.0074 rs1587378 0.0393 rs10510530 0.023 rs13317243 0.0072rs6550755 −0.0193 rs9863976 −0.0219 rs13072262 0.0182 rs322680 −0.0127rs922289 0.0186 rs17026472 −0.0023 rs12630254 −0.013 rs6781673 0.0338rs9853831 −0.0089 rs25506 0.0244 rs2197728 0.0074 rs6799641 0.0074rs999745 −0.0334 rs6806372 0.0178 rs2693477 0.0072 rs7431934 0.0067rs416183 −0.013 rs7639483 0.0287 rs9846284 0.0018 rs2191031 −0.0272rs13314659 0.0141 rs4446245 0.0116 rs17054250 −0.0013 SNP_A- −0.00641880070 rs3864001 −0.0033 rs4083342 −0.0065 rs17054340 −0.0062 rs14617960.0288 rs6445725 0.0154 rs9683127 0.0113 rs641035 0.0195 rs4637258−0.0104 rs11708862 0.005 rs734184 0.0158 rs2366968 0.033 rs17258256−0.0314 rs6785140 −0.0136 rs9834435 −0.0221 rs9840800 0.0292 rs11918950−0.0173 rs2600859 −0.0137 rs17066787 0.0193 rs4254651 −0.0189 rs64454540.0033 rs11705970 0.0079 rs7627319 −0.0332 rs6772684 0.0151 rs12888240.0041 rs13087868 −0.0045 rs4677093 0.0065 rs6549724 −0.0039 rs177451640.0231 rs9852230 0.0188 rs6548639 −0.0086 rs17749340 −0.0005 rs133275800.0184 rs6795503 0.0003 rs17018312 −0.0336 rs2372744 0.0014 rs26392200.0101 rs6548788 0.0261 rs9859573 −0.0115 rs291961 0.0091 rs1883490.0062 rs10511061 0.0284 rs11127978 −0.0104 rs6767207 −0.0136 rs1355226−0.0038 rs724972 −0.0152 rs7631619 −0.0077 rs6785834 −0.0008 rs13068356−0.0039 rs1470574 −0.002 rs16849393 −0.0023 rs16830554 0.0138 rs108046220.0374 rs4928169 −0.0151 rs1318859 0.0119 rs4928057 0.0062 rs1507436−0.0099 rs9822356 −0.0057 rs1241150 0.0035 rs12488048 0.0102 rs98240490.0097 rs11927739 0.0234 rs7643193 0.0055 rs13100164 0.0079 rs4484197−0.0085 rs2715750 −0.0207 rs9815868 0.0066 rs1462302 −0.0075 rs6805801−0.0063 rs2971352 −0.0145 rs6784753 0.018 rs11720141 0.0164 rs1553191−0.0184 rs9289082 −0.0078 rs3772132 0.0003 rs1259494 0.0008 rs76280940.0109 rs2084399 0.0268 rs11707393 0.0221 rs2403313 −0.0217 rs11713445−0.0098 rs995538 −0.0175 rs149862 0.0195 rs16849309 0.0198 rs76328170.0174 rs4616638 −0.0069 rs4527375 −0.0052 rs9811430 −0.0209 rs98653390.0043 rs1195268 −0.0158 rs1026828 −0.0089 rs1026826 −0.0085 rs2889217−0.0035 rs6792834 −0.0085 rs11915439 0.0134 rs10804716 −0.0104 rs15627880.0144 rs1850963 0.0192 rs4679958 0.0299 rs161792 0.0081 rs659379−0.0139 rs701142 0.0245 rs13080908 −0.0203 rs7615026 −0.0046 rs64409950.012 rs344028 −0.0153 rs11914959 −0.0154 rs987724 0.0051 rs98677660.0088 rs11720579 0.0091 rs10451916 0.0255 rs1392799 0.0186 rs98318300.0201 rs11717115 −0.0107 rs6794184 −0.0339 rs1879803 −0.0216 rs1497762−0.0211 rs206313 0.0083 rs206310 0.0049 rs3849450 −0.0328 rs11719240−0.004 rs1407542 −0.0246 rs7628732 −0.0017 rs298755 0.0003 rs10513619−0.0205 rs1440684 −0.0382 rs9990094 0.0064 rs10222648 0.0088 rs124859320.0142 rs6778086 0.0162 rs7623033 −0.0108 rs4855084 0.0099 rs17188166−0.0198 rs2700856 0.0138 rs1002767 0.0142 rs4912577 −0.0032 rs117152220.0383 rs6791954 −0.0422 rs12696555 0.0156 rs9853541 0.0104 rs9746710.0233 rs12330507 0.017 rs16863396 0.0244 rs13084980 −0.0243 rs98793560.0192 rs9853187 0.008 rs1875731 0.0137 rs2708309 −0.011 rs2134634−0.011 rs9854346 0.0113 rs6785291 0.0236 rs11185519 0.0013 rs7649045−0.0229 rs6600769 0.0174 rs1014947 −0.0121 rs1419046 0.0007 rs22514570.0032 rs2471347 0.0134 rs2968684 −0.0403 rs7693293 −0.0044 rs68387920.002 rs750518 0.0006 rs3821920 −0.0204 rs12505562 0.0393 rs168375100.0124 rs16837871 0.02 rs6826497 −0.0068 rs7376617 0.0003 rs73783310.0027 rs6824720 −0.0333 rs10937714 0.0284 rs755403 0.0279 rs4569755−0.0231 rs1344223 −0.0083 rs1048506 −0.0289 rs3775940 −0.0338 rs168773150.0262 rs1558402 0.0237 rs1563254 −0.0033 rs6448930 0.0221 rs6448968−0.0146 rs10489083 −0.0091 rs13113093 −0.014 rs3843422 −0.0102rs12641991 0.0188 rs7663994 −0.0153 rs13128332 −0.02 rs12503223 0.0364rs4698512 0.0139 rs4698515 0 rs604768 −0.0101 rs12507442 0.0262 rs9213710.0253 rs12646671 0.0094 rs3815414 0.0198 rs1006722 0.0149 rs877323−0.0119 rs10489014 −0.011 rs169778 −0.0089 rs1024120 0.0179 rs105171860.0019 rs11930738 −0.0057 rs902658 0.0284 rs874498 0.0261 rs169900310.007 SNP_A- −0.0057 2123334 rs1158162 0.0262 rs16990692 −0.003rs4421010 0.0044 rs7690708 −0.0037 rs6829898 0.0137 rs11735595 −0.0152rs2068783 0.0035 rs7682470 −0.0115 rs10026397 0.0007 rs10026359 −0.0141rs7691499 −0.0088 rs4481267 0.0117 rs17460101 −0.0152 rs12501005 0.0211rs7679812 0.0276 rs6839710 0.0182 rs2048545 −0.0147 rs16858583 0.0236rs4560384 −0.0084 rs12374260 −0.0104 rs1466998 0.0014 rs11725773 0.0151rs17698672 0.0122 rs7677726 0.0078 rs4864471 0.0017 rs11727673 −0.0266rs2646333 0.025 rs11726609 −0.0042 rs17727883 −0.0008 rs17827094 −0.0297rs2570100 0.0098 rs2611162 0.0167 rs1522095 0.0083 rs6554523 0.0189rs10001785 0.0228 rs7689250 −0.0196 rs1551324 −0.0096 rs12501149 −0.0003rs9312096 −0.013 rs7681297 −0.017 rs725761 −0.0147 rs11131312 0.0229rs9685679 0.0097 rs1947275 −0.0208 rs7693819 −0.0065 rs12510678 0.0052rs2347747 −0.0082 rs10517943 −0.0174 rs4146477 −0.0172 rs17735539−0.0466 rs1481261 −0.0094 rs10024794 0.0168 rs2646295 −0.0237 rs13136907−0.0136 rs2130648 −0.0158 rs732317 0.0169 rs11734344 −0.0103 rs6816344−0.0093 rs3113927 0.0068 rs10022778 −0.0056 rs4859755 −0.0039 rs1477314−0.0207 rs1559119 −0.01 rs6534293 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−0.0251 rs2908710 0.0166 rs7201430 −0.0282rs7199390 0.0337 rs11074996 0.0167 rs1230896 0.0134 rs2903305 −0.0031rs2903308 0.01 rs1428402 0.0052 rs1050162 0.0099 rs1840186 −0.0144rs2764776 0.0009 rs1014632 0.0061 rs9922232 0.0151 rs7499763 0.0104rs2521681 0.0173 rs722516 −0.0092 rs6563855 0.0107 rs3944008 −0.0233rs9935379 0.0073 rs7403957 0 rs10521241 −0.0146 rs12599310 −0.0465rs9940629 0.0225 rs12149010 0.011 rs4784376 0.023 rs9929277 −0.0051rs11863682 −0.0103 rs1809348 0.0045 rs37358 0.01 rs37363 0.0144rs2731740 0.0143 rs9926973 0.0091 rs2407755 −0.0035 rs7500302 −0.001rs30888 −0.0156 rs1510212 0.0052 rs2331446 0.003 rs1126179 −0.0022rs254363 −0.0245 rs11642497 −0.0073 rs1862667 0.0276 rs1559307 −0.0004rs1080383 0.0198 rs7198357 −0.0072 rs7203768 −0.01 rs4889197 −0.0026rs7194648 0.0013 rs2866262 −0.0037 rs7185108 −0.0074 rs4528602 0.0079rs17688919 0.0182 rs11646710 0.0107 rs12917864 −0.0095 rs9925569 0.0171rs7197961 0.0198 rs7202180 −0.0049 rs11649462 0.0205 rs2967321 0.0124rs11647182 0.0181 rs1424165 0.0106 rs2042434 −0.0039 rs1035537 −0.0055rs7195745 −0.0138 rs427976 0.0299 rs3751797 0.0153 rs4843404 0.0236rs4843405 0.0168 rs8043893 0.0121 rs8058785 −0.0036 rs4378618 −0.0092rs7203610 −0.0018 rs6540223 0.0264 rs3826067 0.0273 rs2360735 0.0067SNP_A- −0.0373 1832790 rs2131432 −0.0183 rs8072508 0.003 SNP_A- 0.00321833243 rs2955821 0.0105 rs230404 −0.0155 rs150908 0.0194 rs25678720.0032 rs2567871 0.0008 rs2325756 0.0132 rs4262999 0.0192 rs9908162−0.0283 rs7214863 0.0151 rs940854 −0.0306 rs4141200 0.0169 rs4791362−0.0246 rs7210608 0.0029 rs4791489 0.015 rs4791495 −0.0291 rs175606430.0305 rs7212685 0.0223 rs8068578 −0.0228 rs10852820 −0.034 rs15582670.0003 rs956547 −0.0182 rs8080471 −0.0003 rs7212905 0.0051 rs4393623−0.0063 rs6502674 0.014 rs8067882 −0.003 rs8069593 0.0108 rs129434200.016 rs6505282 −0.0239 rs16967400 0.0002 rs7214958 0.0246 rs121008−0.0079 rs11655913 −0.0011 rs712046 0.024 rs8074446 0.0276 rs11095930.014 rs8078723 −0.0404 rs2302777 −0.005 rs1405334 0.0348 rs757274−0.0063 rs9941364 0.0149 rs757102 0.0062 rs17658000 −0.0081 rs1378494−0.0071 rs4796784 0.0242 rs7222316 −0.0072 rs7209177 0.0033 rs12601990−0.0208 rs11713 −0.0127 rs4793035 −0.0117 rs4792814 −0.0427 rs1528072−0.0232 rs7221510 0.0344 rs7405452 0.0334 rs757554 −0.0187 rs80643220.0115 rs10515007 0.0232 rs11079111 0.0015 rs8072786 −0.0251 rs7501602−0.0204 rs6504972 0.0181 rs7220324 0.003 rs4239197 0.0051 rs80676640.0038 rs8073334 −0.0158 rs7209070 −0.0173 rs2111016 0.0173 rs870780−0.0213 rs2585845 0.0097 rs7223491 0.0208 rs6504178 0.0063 rs2665795−0.0018 rs2727330 0.0052 rs17688272 −0.0189 rs894582 0.0079 rs12942924−0.008 rs8073268 0.0201 rs4791051 −0.025 rs7220127 0.0205 rs72194990.0064 rs9904266 0.006 rs16959880 0.0048 rs9910837 0.0268 rs80734770.0116 rs7210863 0.0021 rs8067277 0.0019 rs11652864 −0.0031 rs72261750.0101 rs1093994 −0.0257 rs9911538 −0.0277 rs11077442 −0.0239 rs7216806−0.0155 rs1046896 0.0032 rs2846650 0.002 rs7241142 −0.0258 rs99512590.0019 rs568822 −0.0031 rs7506221 −0.0178 rs1658180 −0.0077 rs8095810−0.0158 rs4797197 0.0098 rs727616 0.0118 rs17388230 −0.0005 rs47985200.0143 rs1016188 0.0121 rs1002715 −0.007 rs649598 −0.0103 rs6193790.0168 rs651568 −0.0137 rs12606001 −0.0167 rs4798749 0.0136 rs6339070.0133 rs10502396 −0.0051 rs1874768 0.0094 rs7231366 −0.0333 rs1284420−0.0053 rs786038 −0.0019 rs786031 −0.0056 rs9957219 0.0194 rs72290530.0117 rs2852741 0.027 rs573845 −0.0172 rs470463 0.0258 rs169439230.0397 rs11564410 0.0181 rs9965582 −0.0071 rs1692481 −0.0267 rs3568270.0096 rs12964420 0.009 rs1031732 −0.024 rs10502582 −0.0262 rs105026620.0132 rs17651514 −0.0219 rs8090179 −0.0167 rs1905517 −0.0125 rs1367837−0.0021 rs8096856 −0.002 rs4362464 0.0179 rs9950114 0.0244 rs129533830.0184 SNP_A- 0.02 4201660 rs11664621 0.0126 rs9304346 0.0153 rs2997190.0142 rs9952908 0.0382 rs7235470 0.0164 rs12955772 0.0201 rs2953264−0.0146 rs2953261 0.0078 rs2879415 −0.0038 rs9962633 0.0206 rs12960274−0.0219 rs16957436 −0.0276 rs969047 0.0144 rs1558536 −0.0132 rs99598000.0145 rs4801058 −0.0223 rs8094838 −0.0236 rs597741 0.0028 rs38654190.0145 rs4058288 0.015 rs12454023 0.0118 rs12457509 −0.0088 rs3744865−0.016 rs2163107 0.0148 rs11665249 0.0192 rs4368253 0.0231 rs6503130.0117 rs8099832 0.012 rs8083437 0.0091 rs1118433 0.007 rs9961166 0.0153rs950408 −0.0124 rs17665435 0.0325 rs683109 0.0029 rs3810031 0.0235rs2850761 −0.0012 rs7227145 −0.0151 rs1455557 0.0023 rs17071220 −0.0228rs1863583 0.0042 rs13370501 0.0112 rs2715282 0.0198 rs2333505 −0.0023rs8088426 −0.0116 rs8088774 −0.016 rs11151403 0.0074 rs7226844 −0.0139rs12960357 0.0208 rs8096331 −0.0164 rs4426448 0.0455 SNP_A- 0.02461836916 rs17082947 0.0204 rs4243328 0.0161 rs17225992 −0.0124 rs18796820.0058 rs2685441 −0.0292 rs1942474 −0.0077 rs12965641 −0.0057 rs80941310.003 rs8089151 0.0346 rs7407812 0.0091 rs11875775 0.0155 rs690227−0.0028 rs10514217 −0.0081 rs1717548 0.003 rs1623269 −0.0139 rs610806−0.0139 rs3809928 0.0028 rs12606550 −0.001 rs7260635 −0.0022 rs415647−0.0163 rs2216662 0.0143 rs1862462 0.0115 rs2431795 0.0122 rs3745597−0.0288 rs7256992 0.045 rs12710152 0.011 rs12982420 0.0263 rs11673570−0.0145 rs11879734 0.0039 rs12609496 −0.0071 rs7249829 0.0199 rs334390.0336 rs3745785 −0.0104 rs7258461 0.0134 rs16967984 −0.016 rs2856860.0239 rs10421478 −0.0208 rs10414846 0.0202 rs1402468 0.0144 rs1620082−0.0258 rs7248248 0.0036 rs11083515 0.0133 rs2159324 0.0109 rs4802322−0.0064 rs12461370 −0.0125 rs2303690 −0.0106 rs10404905 0.0248 rs7533070.0103 rs10401904 0.0012 rs10411879 −0.0189 rs8105809 −0.0001 rs9941465−0.0313 rs302838 0.0393 rs8108715 −0.0146 rs7252632 −0.0349 rs10408146−0.0114 rs10417057 0.0111 rs6118784 −0.005 rs6133763 0.001 rs2143541−0.0059 rs1161237 −0.0007 rs1178015 −0.015 rs6115865 −0.0338 rs2416010.0096 rs6139317 −0.0085 rs6052673 0.0034 rs3746674 0.0328 rs1343178−0.0196 rs990928 0.0206 rs1569874 0.0103 rs6056909 0.0215 rs6074180−0.018 rs6134481 −0.0066 rs6041229 −0.0169 rs6074548 −0.0032 rs6033574−0.002 rs8183260 −0.011 rs6042376 −0.0378 rs3932489 0.0212 rs12258880.0114 rs6080193 −0.0161 rs2208766 −0.0211 rs753213 0 rs6075279 −0.0046rs16979106 0.0018 rs1475126 0.0154 rs6081489 0.0253 rs6035224 0.0001rs1555271 0.0178 rs199790 −0.0099 rs199793 −0.012 rs16984335 0.0107rs7353712 0.022 rs2260455 0.0149 rs6050403 −0.0307 rs1543438 −0.0068rs6088619 0.0048 rs6060669 0.0399 rs8116328 −0.0164 rs1205441 −0.0041rs1119803 −0.0166 rs4811821 −0.0082 rs1002154 −0.0049 rs4810281 0.0086rs941797 0.0214 rs4812566 0.0135 rs2223542 0.0027 rs8119733 −0.0035rs6103041 0.034 rs1973949 −0.0078 rs927058 0.0168 rs459681 −0.0058rs6032544 0.0068 rs376438 0.0057 rs6019032 0.0119 rs2426103 0.0223rs660613 0.0178 rs4591400 0.0216 rs11906291 0.0014 rs230002 0.0132rs6021700 0.0133 rs4809901 −0.0063 rs6013463 −0.0121 rs1403742 −0.0089rs2256452 −0.022 rs6022784 0.0181 rs4811614 0.0151 rs6024333 0.0061rs6070149 −0.023 rs6026574 −0.0104 rs13037047 0.0134 rs2427144 −0.0112rs2822524 0.003 rs2822891 −0.0221 rs2822892 −0.0191 rs412399 0.0124rs420571 −0.0047 rs12482230 0.0082 rs2823806 0.0021 rs414663 −0.016rs11088618 −0.0186 rs2776064 −0.0287 rs17777477 −0.0173 rs1079827 0.0015SNP_A- −0.002 1969384 rs9981165 0.0297 rs2827528 −0.0248 rs28279150.0091 rs1506009 −0.0251 rs2262265 0.0002 rs1892728 −0.0353 rs465318−0.009 rs3017533 0.0204 rs235930 −0.0109 rs2156292 0.0151 rs28309860.0113 rs2831543 −0.0048 rs383576 −0.0105 rs363487 −0.025 rs1016700−0.009 rs2832445 −0.0201 rs2252898 −0.0045 rs2833423 −0.0116 rs2833538−0.015 rs8134837 −0.019 rs2012993 0.0082 rs2833654 −0.0379 rs933122−0.0011 rs2070359 −0.0148 rs7280071 0.011 rs4817889 0.0221 rs28364820.0157 rs1022423 −0.0266 rs1235555 0.0333 rs7282356 0.015 rs7460630.0269 rs2838008 0.0088 rs9305744 0.0091 rs4346474 0.0081 rs8132937−0.0077 rs690260 −0.0366 rs4819962 0.0286 rs5747103 −0.0138 rs3827281−0.0002 rs5748015 −0.0076 rs2800973 0.0116 rs741194 −0.003 rs5997062−0.0227 rs1000815 −0.0133 rs2213758 −0.0196 rs5997178 −0.0247 rs5997228−0.0323 rs761594 0.0453 rs2065057 −0.0147 rs926335 −0.0122 rs2393270.0213 rs130707 −0.019 rs9607337 −0.0335 rs131838 −0.0108 rs22840600.008 rs738477 0.0066 rs738479 −0.0248 rs12628020 −0.0221 rs5765532−0.0332 rs5768257 0.0205 rs5766999 0.0136 rs5770018 −0.0107

All publications mentioned in the above specification are hereinincorporated by reference. Various modifications and variations of thedescribed methods and system of the invention will be apparent to thoseskilled in the art without departing from the scope and spirit of theinvention. Although the invention has been described in connection withspecific preferred embodiments, it should be understood that theinvention as claimed should not be unduly limited to such specificembodiments. Indeed, various modifications of the described modes forcarrying out the invention which are obvious to those skilled ingenetics, diagnostic assays, molecular biology or related fields areintended to be within the scope of the following claims.

1. A method for diagnosing an autism spectrum disorder (ASD), orpredisposition to develop an ASD, in a subject, which comprises the stepof investigating a set of single nucleotide polymorphisms (SNPs) in asample from the subject, wherein the number of SNPs in the set is suchthat the method can diagnose ASD with at least 70% accuracy.
 2. A methodaccording to claim 1, wherein the set comprises at least 1500 SNPs fromthe list given in Table
 3. 3. A method according to claim 2, wherein theset comprises at least 2300 SNPs from the list given in Table
 3. 4. Amethod according to claim 2, wherein the set comprises all 3126 SNPsgiven in Table
 3. 5. A method according to claim 1, wherein the setcomprises at least 70% of the SNPs weighted at least ±0.01 in Table 3.6. A method according to claim 1, wherein the set comprises between 1500and 4500 SNPs.
 7. A method according to claim 1, wherein the setcomprises between 2300 and 3900 SNPs.
 8. A method according to claim 1,wherein the set comprises between 3000 and 3300 SNPs.
 9. A kit fordiagnosing an autism spectrum disorder (ASD), or predisposition todevelop an ASD, in a subject, which comprises a plurality of primerpairs or probes capable of investigating a set of single nucleotidepolymorphisms (SNPs) in a sample from the subject, wherein the set ofSNPs comprises at least 1500 SNPs from the list given in Table
 3. 10. Akit according to claim 9, wherein the plurality of probes is immobilisedon a solid support.
 11. A method for preparing a kit according to claim10 which comprises the step of immobilising the plurality of probes onto a solid support.